Rosuvastatin
is the only statin that has shown life-threatening rhabdomyolysis in pre-approval
stage of clinical trials, says Dr Krishan Maggon in the first part of
the article

Rosuvastatin (Crestor, Astra Zeneca) was hailed as a superstatin,
expected to be more effective and safer than atorvastatin (Lipitor) during its
development and at one time had peak projected sales of $5 billion. The drug
was expected to make up for the lost sales and profits after patent expiry of
omeprazole (Losec, Prilosec) for AstraZeneca.

Current market projections by analysts were scaled back to peak sales of $3
billion due to slow market uptake, lack of long term safety and outcome data
and strong competition from existing and other combination products in development.
Worldwide sales were $129 million (USA $62 million) in 2003. In comparison,
another lipid lowering product ezetimib (Zetia) introduced in 2003 had much
faster uptake with sales of $600 million.

Rosuvastatin (Crestor) is the sixth cholesterol lowering statin
drug on the US market. The other members of the statin family are atorvastatin
(Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), pravastatin (Pravachol)
and simvastatin (Zocor). These drugs are only approved to be used along with
a low-cholesterol diet and an exercise programme to lower cholesterol.

Cerivastatin (Baycol, Lipobay) was introduced in the USA market by Bayer in
1997 and was withdrawn in August 2001. Cerivastatin was removed from the market
because of at least 31 reports of fatal rhabdomyolysis, an adverse reaction
involving the destruction of muscle tissue that can lead to kidney failure.
In September 2003, Bayer announced 100 deaths linked to the use of Baycol and
settlement of 1342 lawsuits for $442 million.

Rosuvastatin was initially discovered and developed by the Japanese pharmaceutical
company Shionogi, Osaka and in-licensed to AstraZeneca in April 1998. AstraZeneca
originally filed its application with the FDA to market rosuvastatin in June
2001. The application was delayed when the company halted clinical trials worldwide
after reports of kidney damage and muscle weakness (an early signal for rhabdomyolysis)
in clinical trials in patients taking 80 milligrams of the drug per day.

The FDA asked AstraZeneca to generate and submit additional clinical trial
data at 20 and 40mg doses in June 2002. The company terminated development of
the 80mg dose because of the safety problems and FDA refusal. The Netherlands
was the first country to grant approval for rosuvastatin in November 2002 and
the drug has now been approved in 51 countries. It was first marketed in Canada
in February 2003, and over one million patients have now been treated with the
drug with over two million prescriptions dispensed worldwide.

The FDA Advisory Committee unanimously recommended for rosuvastatin approval
in July 2003. The regulatory authorities of some European countries withdrew
from the EMEA mutual recognition procedure to grant market authorisation. The
drug is now approved in Ireland, Finland, Denmark, Sweden, Iceland and the UK.
The FDA approved rosuvastatin on August 12, 2003, (5, 10, 20, and 40 mg tablets)
based on multiple trials of at least 6 weeks duration in which rosuvastatin
treatment was compared to placebo and other marketed statins.

In these trials, rosuvastatin reduced total-cholesterol, LDL-C, and TG and increased
HDL-C with therapeutic response occurring within one week and maximum response
seen at four weeks. ICH guidelines require, for long-term treatment of non-life-threatening
conditions, 1,500 patients treated with the drug for safety, 300-600 treated
for at least six months for efficacy and at least 100 for 12 months. FDA has
required 200 patients treated for one year.

AstraZeneca total patient exposure in clinical trials submitted for approval
for rosuvastatin (12,500) was considerably greater than the 2,000 to 3,000 patients
submitted for most of the currently approved statins. Galaxy is the umbrella
name for at least 16 clinical trials designed to investigate the efficacy of
rosuvastatin in various clinical settings.

Rosuvastatin clinical data in the treatment of primary hypercholesterolemia
was published in Annals of Pharmacotherapy (January 2002). The pooled data suggested
that at dosages of 1-40 mg/day, rosuvastatin significantly reduced total cholesterol
and low-density-lipoprotein cholesterol (LDL-C) and produced treatment benefits
on other lipid parameters as well. The LDLC reduction ranged from -33
per cent at 1mg and -62 per cent at 40 mg. Increases in HDL-C were most notable
in those patients with HDL-C, 34 mg/dL at entry. Similarly, reductions in TGs
were more pronounced in patients whose baseline TG levels exceeded 200 mg/dL.

The drug was found to be well tolerated and superior to other statins on the
mg to mg basis and other cholesterol-lowering agents. Rosuvastatin clinical
data was published in the American Heart Journal, American Journal of Cardiology,
and the Journal of Cardiovascular Risk (Olsson AG. Statin therapy and reductions
in low-density lipoprotein cholesterol: initial clinical data on the potent
new statin Rosuvastatin. Am J Cardiol 2001; 87: 33B-36B).

Patients (2,431) with hypercholesterolemia, were randomised to treatment with
rosuvastatin 10, 20, 40, or 80 mg; atorvastatin 10, 20, 40, or 80 mg; simvastatin
10, 20, 40, or 80 mg; or pravastatin 10, 20, or 40 mg. At six weeks, across-dose
analyses showed that rosuvastatin 10 to 80 mg reduced LDL cholesterol by a mean
of 8.2 per cent more than atorvastatin 10 to 80 mg, 26 per cent more than pravastatin
10 to 40 mg, and 12 per cent to 18 per cent more than simvastatin 10 to 80 mg
(all p ,0.001).

Across dose ranges, rosuvastatin reduced total cholesterol more significantly
than all comparators and triglycerides more than simvastatin and pravastatin
and more patients achieved LDL goals. Rosuvastatin was, dose for dose, more
effective at achieving national guideline targets for lipid concentrations than
its competitors. Drug tolerability was similar across treatments (Jones et al.
Am J Cardiol 2003;92:152-160 and Current Medical Research and Opinions 2003;
19: P1-P10).

New drugs in development

Pfizer is spending $1 billion to buy Esperion and develop one of its drugs to
raise HDL. Torcetrapib, a partial cholesterol ester transfer protein blocker,
is in phase III trials in combination with atorvastatin (Lipitor). If effective,
torcetrapib will produce enough HDL to remove plaque from arteries, and decrease
the risk of heart attack and stroke. Recent study published in JAMA raises some
questions about the benefits of raising HDL levels. Torcetrapib is will be sold
in combination with Lipitor.

Pfizer is also developing a combination product that combines atorvastatin and
amlodipine. The combination pills are going to be blockbusters and could preserve
the Lipitor franchise for another decade after the drug loses patent protection
in 2010. The current perception is that combination of agents with different
modes of action to reduce lipids, cholesterol, free fatty acids and triglycerides
like ACAT inhibitors, bile acid sequestrants and lipid absorption inhibitors
will provide marketing blockbusters and prolong the life of statin patents.

In 2003, atorvastatin and simvastatin were the worlds second and third
best-selling drugs after erythropoietin. By 2008, the hyperlipidemia market
will be valued at more than $40 billion. Generics have already entered the European
market as Mercks Mevacor and Zocor have lost patent protection in different
EU countries since 2002. Pravachol will lose protection in Europe by 2004, and
US patent expiry of all three statins will take place in 2006.

The superstatins  rosuvastatin (Crestor, AstraZeneca) and pitavastatin
(Sankyo)  have proved superior to the first-generation agents. Rosuvastatin
was launched in selected European countries, USA and Canada in 2003. Sankyo
has filed for approval of pitavastatin in Japan (expected 2004), and in the
United States and Europe (expected 2005). Novartis will market pitavastatin
in Europe, while the marketing partner in USA is not decided.

Other cholesterol reducers that has generated substantial revenues include ezetimibe
(Merck/Schering-Ploughs Zetia), avasimibe and torcetrapib (Pfizer), and
combinations of new and existing products. Ezetimibe is a selective intestinal
cholesterol absorption inhibitor that was launched in late 2002 in the United
States and Europe and had sales of $600 million in 2003 making it one of the
most successful market launch. Wall street analysts forecast for Zetia range
from $2 billion to 10 billion.

In clinical trials of ezetimibe co-administered with simvastatin, there was
no increased incidence of myopathy or rhabdomyolysis associated with ezetimibe/simvastatin.
Ezetimibe is expected to make up for revenues loss due to patent expiry of simvastatin
by 2006.

Avasimibe is an acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor that could
receive approval in 2004. Ezetimibe is the more significant product: the Merck/Schering-Plough
joint venture is also developing a combination of ezetimibe and simvastatin
that produces enhanced lipid-lowering effects. The combination product will
be launched in 2005.

Rosuvastatin adverse reactions

The most frequent side effects seen in patients treated with rosuvastatin included
muscle aches, stomach pain, constipation, nausea, and weakness. In rare instances,
severe muscle pain and muscle weakness resulting in kidney damage have been
associated with statin drugs. Patients should be monitored for abnormalities
of liver function before treatment, at 12 weeks following initial therapy and
with any elevation of dose. Monitoring is recommended periodically thereafter.

Rosuvastatin causes abnormal elevations in urine protein and blood that are
signals for serious kidney toxicity; other statins are not associated with this
risk of kidney toxicity. Rosuvastatin is the only statin that has shown life-threatening
rhabdomyolysis in pre-approval clinical trials. Development of severe myopathy
or rhabdomyolysis requiring hospitalisation for IV hydration occurred only at
the 80 mg dose.

The incidences of CK elevations and myopathy in clinical trials of rosuvastatin
5 to 40 mg were between 0.2 to 0.4 per cent and 0.1 to 0.2 per cent, respectively,
which are similar to rates seen with other currently approved statins. Patients
receiving rosuvastatin had an increased rate of developing proteinuria with
and without hematuria, and in a small percentage of these cases the findings
were persistent and associated with an increase in serum creatinine. Proteinuria
was most pronounced at the 80 mg dose and the rate decreased in patients back-titrated
from 80 to 40 mg suggesting reversibility.

There were two cases of renal failure and one case of renal insufficiency in
patients receiving rosuvastatin 80 mg associated with proteinuria and hematuria.
Renal biopsies in two of these cases suggested tubular inflammation and necrosis.
The risks of muscle and renal toxicity appear dose-related and are clearly evident
at the 80 mg dose. No patients treated with rosuvastatin 20 mg daily had drug
levels in the range observed with clinical toxicity.

A few patients treated with rosuvastatin 40 mg (2 per cent) had drug levels
within this range and a greater proportion of patients treated with 80 mg (33
per cent) achieved drug levels 50 ng/mL. This analysis suggests a potential
threshold in the drug level at which risks of muscle and renal toxicity are
increased. Treatment at the 20 mg and lower doses does not appear to raise drug
levels into this range of concern. However, clinical situations
(e.g. drug-drug interactions, special populations, Asians) which may increase
drug levels require careful consideration as patients in these settings may
be exposed to drug levels beyond what is typical for the 20 and 40 mg doses.(To
be concluded)The writer is can be contacted at maggonk@lycos.com